•COVID-19 patients show a broad spectrum of neurological manifestations.•SARS-CoV-2 is scarcely detected in cerebrospinal fluid.•Viral-triggered autoimmune responses may lead to neurological ...symptoms.•Immunotherapy should be considered in CSF autoantibody-positive Covid-19 patients.
COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.
Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.
Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.
The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.
Background
Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A‐IV (apoA‐IV) has antiatherogenic, ...antioxidative, anti‐inflammatory and antithrombotic properties and levels increase significantly during the course of CKD.
Objectives
We aimed to investigate the association between apoA‐IV and all‐cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.
Methods
This was a prospective cohort study including 5141 Caucasian patients with available apoA‐IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30–60 ml/min/1.73m2 or an eGFR >60 ml/min/1.73m2 in the presence of overt proteinuria. Median follow‐up was 6.5 years. The association of apoA‐IV with comorbidities at baseline and endpoints during follow‐up was modelled adjusting for major confounders.
Results
Mean apoA‐IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA‐IV quartile had the lowest high‐sensitivity C‐reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA‐IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval CI 0.72–0.86, p = 0.0000003). During follow‐up, each 10 mg/dl higher apoA‐IV was significantly associated with a lower risk for all‐cause mortality (600 cases, hazard ratio HR = 0.81, 95% CI 0.73–0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79–0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73–0.96, p = 0.01).
Conclusions
These data support a link between elevated apoA‐IV concentrations and reduced inflammation in moderate CKD. ApoA‐IV appears to be an independent risk marker for reduced all‐cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
Accurately collected 24-hour urine collections are presumed to be valid for estimating salt intake in individuals. We performed 2 independent ultralong-term salt balance studies lasting 105 (4 men) ...and 205 (6 men) days in 10 men simulating a flight to Mars. We controlled dietary intake of all constituents for months at salt intakes of 12, 9, and 6 g/d and collected all urine. The subjects' daily menus consisted of 27 279 individual servings, of which 83.0% were completely consumed, 16.5% completely rejected, and 0.5% incompletely consumed. Urinary recovery of dietary salt was 92% of recorded intake, indicating long-term steady-state sodium balance in both studies. Even at fixed salt intake, 24-hour urine collection for sodium excretion (UNaV) showed infradian rhythmicity. We defined a ±25 mmol deviation from the average difference between recorded sodium intake and UNaV as the prediction interval to accurately classify a 3-g difference in salt intake. Because of the biological variability in UNaV, only every other daily urine sample correctly classified a 3-g difference in salt intake (49%). By increasing the observations to 3 consecutive 24-hour collections and sodium intakes, classification accuracy improved to 75%. Collecting seven 24-hour urines and sodium intake samples improved classification accuracy to 92%. We conclude that single 24-hour urine collections at intakes ranging from 6 to 12 g salt per day were not suitable to detect a 3-g difference in individual salt intake. Repeated measurements of 24-hour UNaV improve precision. This knowledge could be relevant to patient care and the conduct of intervention trials.
Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine ...levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
Abstract
With an urgent need for bedside imaging of coronavirus disease 2019 (COVID-19), this study’s main goal was to assess inter- and intraobserver agreement in lung ultrasound (LUS) of COVID-19 ...patients. In this single-center study we prospectively acquired and evaluated 100 recorded ten-second cine-loops in confirmed COVID-19 intensive care unit (ICU) patients. All loops were rated by ten observers with different subspeciality backgrounds for four times by each observer (400 loops overall) in a random sequence using a web-based rating tool. We analyzed inter- and intraobserver variability for specific pathologies and a semiquantitative LUS score. Interobserver agreement for both, identification of specific pathologies and assignment of LUS scores was fair to moderate (e.g., LUS score 1 Fleiss’ κ = 0.27; subpleural consolidations Fleiss’ κ = 0.59). Intraobserver agreement was mostly moderate to substantial with generally higher agreement for more distinct findings (e.g., lowest LUS score 0 vs. highest LUS score 3 (median Fleiss’ κ = 0.71 vs. 0.79) or air bronchograms (median Fleiss’ κ = 0.72)). Intraobserver consistency was relatively low for intermediate LUS scores (e.g. LUS Score 1 median Fleiss’ κ = 0.52). We therefore conclude that more distinct LUS findings (e.g.,
air bronchograms
,
subpleural consolidations
) may be more suitable for disease monitoring, especially with more than one investigator and that training material used for LUS in point-of-care ultrasound (POCUS) should pay refined attention to areas such as
B-line
quantification and differentiation of intermediate LUS scores.
The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the ...hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.
Acute kidney injury (AKI) is a major health issue, the outcome of which depends primarily on damage and reparative processes of tubular epithelial cells. Mechanisms underlying AKI remain incompletely ...understood, specific therapies are lacking and monitoring the course of AKI in clinical routine is confined to measuring urine output and plasma levels of filtration markers. Here we demonstrate feasibility and potential of a novel approach to assess the cellular and molecular dynamics of AKI by establishing a robust urine-to-single cell RNA sequencing (scRNAseq) pipeline for excreted kidney cells via flow cytometry sorting. We analyzed 42,608 single cell transcriptomes of 40 urine samples from 32 patients with AKI and compared our data with reference material from human AKI post-mortem biopsies and published mouse data. We demonstrate that tubular epithelial cells transcriptomes mirror kidney pathology and reflect distinct injury and repair processes, including oxidative stress, inflammation, and tissue rearrangement. We also describe an AKI-specific abundant urinary excretion of adaptive progenitor-like cells. Thus, single cell transcriptomics of kidney cells excreted in urine provides noninvasive, unprecedented insight into cellular processes underlying AKI, thereby opening novel opportunities for target identification, AKI sub-categorization, and monitoring of natural disease course and interventions.
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The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the ...significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection.
Single center analysis of 417 deceased donor kidney recipients (age>18; transplantation date 1/2008-2/2015). Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year.
No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included (HR 1.71, 95%CI 1.16,2.53) or excluded (HR 1.79, 95%CI 1.13,2.84).
DGF is significantly associated with rejection-with or without borderline changes-within the first year.
Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase ...hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.
In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.
Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval CI, 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.
The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)
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